Although stem cells hold considerable promises for the treatment of a number of devastating diseases (e.g. cardiovascular diseases, neurodegenerative diseases, diabetes and cancers), obstacles such as control of stem cell fate/function, immuno-rejection, and limited cell sources must be overcome before their therapeutic potentials can be realized. Recent studies have suggested that tissue-specific somatic cells may overcome their intrinsic lineage-restriction to de-differentiate or trans-differentiate (i.e. reprogramming) upon exposure to a specific set of signals (or ectopic expression of master transcription factors) in vitro and in vivo. Reprogramming of various rodent and human somatic cells to pluripotent ESC-like cells (i.e. induced pluripotent/iPS cells) has recently been achieved by viral transduction of four transcription factors (e.g. Oct4, cMyc, Sox2 and Klf4). More recently, we have reported that small molecules can replace certain transcription factors as well as substantially improve reprogramming efficiency and kinetics in generating iPS cells, and developed a method of generating and using recombinant cell-penetrating proteins to generate iPS cells without using any genetic materials and genetic manipulation (please see our preliminary results). With those proof-of-principle demonstrations, we propose to further develop/optimize the chemically defined, protein and small molecule-based reprogramming process in human cells to have highly robust and efficient method and to further in-depth characterize those cells.